The Human Immunodeficiency Virus (HIV) is a causative agent of AIDS and related disorders. The virus contains a protease (HIV-PR) that cleaves the polyprotein precursors encoded by gag and pol genes to mature proteins needed for the production of infectious HIV virus. Inhibition of this process is regarded as a promising approach for the treatment of AIDS. The X-ray crystallography has revealed that the HIV-PR is a symmetric dimer with each monomer consisting of 99 amino acids. The active site contains two aspartic residues, one from each unit. There is no covalent bonding in the dimer. Dissociation of the dimer to monomers yields an inactive protein. Experiments have found that the stability of the dimer against dissociation depends on pH, salt concentrations and other physical factors. Reported dissociation constant varies over a 10(4) fold. Molecular modeling of the dimer dissociation and its pH dependence will provide a better understanding. Molecular modeling will be used to investigate the pH dependence of dimer dissociation of HIV-PR. The Poisson-Boltzman method will he used to predict the shift in pKa's of titrable residues in the protease and the average charge in the protease at given pH. The dissociation of the dimer will be modeled by two different routes, a folded dimer to two unfolded monomers, and a folded dimer to two folded monomers. Proton linkage theory will be used to estimate the change in the free energy of dissociation as a function of pH. Residues that undergo significant change of charge in a given pH range will be identified. Molecular dynamics simulations of HIV-PR with these residues at different protonation states will be performed to have a closer examination about the effect of these residues on dimer stability. The procedures will be applied to native HIV-PR, HIV-PR bound with inhibitors and substrates, and drug resistant mutations of the HIV-PR. The results will provide a better understanding about dimer dissociation of native HIV-PR and the mutants of HIV-PR.